Effect of atherosclerosis on 5-year risk of major vascular events in patients with transient ischaemic attack or minor ischaemic stroke: an international prospective cohort study.
The prevalence of atherosclerosis and the long-term risk of major vascular events in people who have had a transient ischaemic attack or minor ischaemic stroke, regardless of the causal relationship between the index event and atherosclerosis, are not well known. In this analysis, we applied the ASCOD (atherosclerosis, small vessel disease, cardiac pathology, other causes, and dissection) grading system to estimate the 5-year risk of major vascular events according to whether there was a causal relationship between atherosclerosis and the index event (ASCOD grade A1 and A2), no causal relationship (A3), and with or without a causal relationship (A1, A2, and A3). We also aimed to estimate the prevalence of different grades of atherosclerosis and identify associated risk factors. We analysed patient data from TIAregistry.org, which is an international, prospective, observational registry of patients with a recent (within the previous 7 days) transient ischaemic attack or minor ischaemic stroke (modified Rankin Scale score of 0-1) from 61 specialised centres in 21 countries in Europe, Asia, the Middle East, and Latin America. Using data from case report forms, we applied the ASCOD grading system to categorise the degree of atherosclerosis in our population (A0: no atherosclerosis; A1 or A2: atherosclerosis with stenosis ipsilateral to the cerebral ischaemic area; A3: atherosclerosis in vascular beds not related to the ischaemic area or ipsilateral plaques without stenosis; and A9: atherosclerosis not assessed). The primary outcome was a composite of non-fatal stroke, non-fatal acute coronary syndrome, or cardiovascular death within 5 years. Between June 1, 2009, and Dec 29, 2011, 4789 patients were enrolled to TIAregistry.org, of whom 3847 people from 42 centres participated in the 5-year follow-up; 3383 (87·9%) patients had a 5-year follow-up visit (median 92·3% [IQR 83·4-97·8] per centre). 1406 (36·5%) of 3847 patients had no atherosclerosis (ASCOD grade A0), 998 (25·9%) had causal atherosclerosis (grade A1 or A2), and 1108 (28·8%) had atherosclerosis that was unlikely to be causal (grade A3); in 335 (8·7%) patients, atherosclerosis was not assessed (grade A9). The 5-year event rate of the primary composite outcome was 7·7% (95% CI 6·3-9·2; 101 events) in patients categorised with grade A0 atherosclerosis, 19·8% (17·4-22·4; 189 events) in those with grade A1 or A2, and 13·8% (11·8-16·0; 144 events) in patients with grade A3. Compared with patients with grade A0 atherosclerosis, patients categorised as grade A1 or A2 had an increased risk of the primary composite outcome (hazard ratio 2·77, 95% CI 2·18-3·53; p<0·0001), as did patients with grade A3 (1·87, 1·45-2·42; p<0·0001). Except for age, male sex, and multiple infarctions on neuroimaging, most of the risk factors that were identified as being associated with grade A1 or A2 atherosclerosis were modifiable risk factors (ie, hypertension, dyslipidaemia, overweight, smoking cigarettes, and low physical activity; all p values <0·025). In patients with transient ischaemic attack or minor ischaemic stroke, those with atherosclerosis have a much higher risk of major vascular events within 5 years than do those without atherosclerosis. Preventive strategies addressing complications of atherosclerosis should focus on individuals with atherosclerosis rather than grouping together all people who have had a transient ischaemic attack or minor ischaemic stroke (including those without atherosclerosis). AstraZeneca, Sanofi, Bristol Myers Squibb, SOS Attaque Cérébrale Association.


Ataluren-driven restoration of Shwachman-Bodian-Diamond syndrome protein function in Shwachman-Diamond syndrome bone marrow cells.
Shwachman-Diamond syndrome (SDS) is a rare inherited recessive disease mainly caused by mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene, which encodes for the homonymous protein SBDS, whose function still remains to be fully established. SDS affects several organs causing bone marrow failure, exocrine pancreatic insufficiency, skeletal malformations, and cognitive disorders. About 15% of SDS patients develop myelodysplastic syndrome (MDS) and are at higher risk of developing acute myeloid leukemia (AML). Deficiency in SBDS expression has been associated with increased apoptosis and lack of myeloid differentiation in bone marrow hematopoietic progenitors. Importantly, most SDS patients carry nonsense mutations in SBDS. Since ataluren is a well-characterized small molecule inhibitor that can suppress nonsense mutations, here, we have assessed the efficacy of this drug in restoring SBDS expression in hematopoietic cells obtained from a cohort of SDS patients. Remarkably, we show that ataluren treatment readily restores SBDS protein expression in different cell types, particularly bone marrow stem cells. Furthermore, ataluren promotes myeloid differentiation in hematopoietic progenitors, reduces apoptotic rate in primary PBMCs, and brings mammalian target of rapamycin phosphorylation levels back to normal in both lymphoblasts and bone marrow mesenchymal stromal cells (BM-MSCs). Since a specific therapy against SDS is currently lacking, these results provide the rationale for ataluren repurposing clinical trials.


Origins of the Canadian school of surgery.
Since its inception 50 years ago, the Canadian Journal of Surgery has published articles under the banner "History of Canadian Surgery." Because no comprehensive history of surgery in this country has yet been written, these articles may provide its basis. The Canadian Journal of Surgery was searched from October 1957 to August 2007 for articles on the practice of surgery in Canada before 1957. Articles regarding the development of surgery in provinces, universities, hospitals and surgical specialty societies were included, as well as biographies and obituaries of surgeons. Thirty-six articles dealing with the lives of 57 Canadian surgeons were located. Three periods of Canadian surgery were covered: the French regime (1535-1759), the transition period (1759-1870) and the early modern period (1870-1945). The review shows that persistent efforts were made in Canada to develop surgical education and to regulate the practice of surgery. Isolation forced a spirit of adaptability that led to innovation and progress. The practice of surgery in Canada today can be traced back to contributions made by pioneering surgeons over the entire history of modern Canada. An archive of materials related to the history of surgery in Canada is being created at www.historyofsurgery.ca to facilitate further research.


The PPAR-microbiota-metabolic organ trilogy to fine-tune physiology.
The human gut is colonized by commensal microorganisms, predominately bacteria that have coevolved in symbiosis with their host. The gut microbiota has been extensively studied in recent years, and many important findings on how it can regulate host metabolism have been unraveled. In healthy individuals, feeding timing and type of food can influence not only the composition but also the circadian oscillation of the gut microbiota. Host feeding habits thus influence the type of microbe-derived metabolites produced and their concentrations throughout the day. These microbe-derived metabolites influence many aspects of host physiology, including energy metabolism and circadian rhythm. Peroxisome proliferator-activated receptors (PPARs) are a group of ligand-activated transcription factors that regulate various metabolic processes such as fatty acid metabolism. Similar to the gut microbiota, PPAR expression in various organs oscillates diurnally, and studies have shown that the gut microbiota can influence PPAR activities in various metabolic organs. For example, short-chain fatty acids, the most abundant type of metabolites produced by anaerobic fermentation of dietary fibers by the gut microbiota, are PPAR agonists. In this review, we highlight how the gut microbiota can regulate PPARs in key metabolic organs, namely, in the intestines, liver, and muscle. Knowing that the gut microbiota impacts metabolism and is altered in individuals with metabolic diseases might allow treatment of these patients using noninvasive procedures such as gut microbiota manipulation.-Oh, H. Y. P., Visvalingam, V., Wahli, W. The PPAR-microbiota-metabolic organ trilogy to fine-tune physiology.


Long-term disease-free survival in patients with angioimmunoblastic T-cell lymphoma after high-dose chemotherapy and autologous stem cell transplantation.
Patients with angioimmunoblastic T-cell lymphoma (AIL) have a poor prognosis with conventional treatment. We initiated an EBMT-based survey studying the impact of high-dose chemotherapy (HDCT) and autologous hematopoietic stem cell transplantation in patients with AIL. Data on 29 patients, who were transplanted between 1992 and 1998 in 16 transplant centers, were collected on standardized documentation forms. The median age at transplantation was 53 years. HDCT was given as part of 1st-line therapy (N=14; 48%) or 2nd/3rd-line therapy (N=15; 52%). Regimens for the mobilization of peripheral blood stem cells (PBSC) included VIPE (N=7; 26%), DexaBEAM (N=6; 22%), CHOP-like regimens (N=6; 22%), other regimens (N=5; 19%) or alternatively growth factor alone (N=3; 11%). The median yield of PBSC was 3.8x106 CD34+cells/kg. Two patients received autologous bone marrow. The HDCT consisted of BEAM-type regimens in 16 patients, ICE-type regimens in 7, and other regimens in 6 patients. There was one treatment-related death. The rate of complete remissions increased from 45% before HDCT to 76% after HDCT. As of January 2003, after a median observation time of living patients of 5 years (range 2.5 to 10 years), 14 patients have died (13 from progressive disease), and 15 patients are alive. The probability of 5-year overall and event-free survival was 44% (95% CI, 22% to 66%) and 37% (95% CI, 17% to 57%), respectively. Long-term disease-free survival was observed in patients transplanted during 1st-line treatment as well as in the context of 2nd/3rd-line therapy. There is evidence that AIL is susceptible to high-dose chemotherapy. HDCT and autologous stem cell transplantation should be considered in selected patients with AIL.


Molecular Cytogenetic Analysis of Deschampsia antarctica Desv. (Poaceae), Maritime Antarctic.
Deschampsia antarctica Desv. (Poaceae) (2n = 26) is one of the two vascular plants adapted to the harshest environment of the Antarctic. Although the species is a valuable model for study of environmental stress tolerance in plants, its karyotype is still poorly investigated. We firstly conducted a comprehensive molecular cytogenetic analysis of D. antarctica collected on four islands of the Maritime Antarctic. D. antarctica karyotypes were studied by Giemsa C- and DAPI/C-banding, Ag-NOR staining, multicolour fluorescence in situ hybridization with repeated DNA probes (pTa71, pTa794, telomere repeats, pSc119.2, pAs1) and the GAA simple sequence repeat probe. We also performed sequential rapid in situ hybridization with genomic DNA of D. caespitosa. Two chromosome pairs bearing transcriptionally active 45S rDNA loci and five pairs with 5S rDNA sites were detected. A weak intercalary site of telomere repeats was revealed on the largest chromosome in addition to telomere hybridization signals at terminal positions. This fact confirms indirectly the hypothesis that chromosome fusion might have been the cause of the unusual for cereals chromosome number in this species. Based on patterns of distribution of the examined molecular cytogenetic markers, all chromosomes in karyotypes were identified, and chromosome idiograms of D. antarctica were constructed. B chromosomes were found in most karyotypes of plants from Darboux Island. A mixoploid plant with mainly triploid cells bearing a Robertsonian rearrangement was detected among typical diploid specimens from Great Jalour Island. The karyotype variability found in D. antarctica is probably an expression of genome instability induced by environmental stress factors. The differences in C-banding patterns and in chromosome distribution of rDNA loci as well as homologous highly repeated DNA sequences detected between genomes of D. antarctica and its related species D. caespitosa indicate that genome reorganization involving coding and noncoding repeated DNA sequences had occurred during the divergence of these species.


Technical and scale efficiency in the delivery of child health services in Zambia: results from data envelopment analysis.
Despite tremendous efforts to scale up key maternal and child health interventions in Zambia, progress has not been uniform across the country. This raises fundamental health system performance questions that require further investigation. Our study investigates technical and scale efficiency (SE) in the delivery of maternal and child health services in the country. The study focused on all 72 health districts of Zambia. We compiled a district-level database comprising health outcomes (measured by the probability of survival to 5 years of age), health outputs (measured by coverage of key health interventions) and a set of health system inputs, namely, financial resources and human resources for health, for the year 2010. We used data envelopment analysis to assess the performance of subnational units across Zambia with respect to technical and SE, controlling for environmental factors that are beyond the control of health system decision makers. Nationally, average technical efficiency with respect to improving child survival was 61.5% (95% CI 58.2% to 64.8%), which suggests that there is a huge inefficiency in resource use in the country and the potential to expand services without injecting additional resources into the system. Districts that were more urbanised and had a higher proportion of educated women were more technically efficient. Improved cooking methods and donor funding had no significant effect on efficiency. With the pressing need to accelerate progress in population health, decision makers must seek efficient ways to deliver services to achieve universal health coverage. Understanding the factors that drive performance and seeking ways to enhance efficiency offer a practical pathway through which low-income countries could improve population health without necessarily seeking additional resources.


Effects of hormone therapy on depressive symptoms and cognitive functions in women with Alzheimer disease: a 12 month randomized, double-blind, placebo-controlled study of low-dose estradiol and norethisterone.
To elucidate the effects of low-dose 17beta-estradiol and norethisterone (hormone therapy [HT]) versus placebo in women with Alzheimer Disease (AD) on cognition, depressive symptoms, and activities of daily living. A 12-month randomized, double-blind, placebo-controlled study, stratified by apolipoprotein E (ApoE) genotype (with versus without the epsilon4 allele), duration of education (< or =9 versus >9 years), and age (< or =75 versus >75 years) performed during 2000-2004. Ambulatory memory clinic in a general hospital. Sixty-five female outpatients aged 65-89 years who met criteria for probable AD according to Diagnostic and Statistical Manual of Mental Disorders, fourth edition and International Classification of Diseases, tenth edition. Ten patients were excluded, resulting in 55 participants who had at least one posttreatment efficacy evaluation. Randomly assigned to receive either 1-mg estradiol and 0.5-mg norethisterone or placebo once daily. Cognitive variables were the Dementia Rating Scale, tests from Consortium to Establish a Registry for AD, Global Deterioration Scale (GDS) and Barthel Index. When only treatment effects were compared by analysis of variance, there were nonsignificant differences between treatment groups for all efficacy variables. A linear model analysis, including stratifying factors in addition to treatment in the model, revealed a significant main effect on mood. The depressive symptoms were lower in the HT group than in the placebo group. Those treated with HT without the ApoE epsilon4 allele had better mood, Word Learning Memory score, and GDS score. Those in the HT group with a higher level of education obtained a better GDS score. Adverse events did not differ between the groups. HT interacts with ApoE genotype in women with AD. Women without an ApoE epsilon4 allele may get better mood and cognition with HT. HT may reduce depressive mood and give less cognitive decline.


Evaluation of the protective efficacy of a recombinant dengue envelope B domain fusion protein against dengue 2 virus infection in mice.
A recombinant protein containing part of the dengue (DEN) 2 envelope protein was evaluated as a subunit immunogen for vaccination against DEN virus infection. A gene fragment encoding amino acids 298-400 (B domain) of the DEN-2 virus envelope was expressed as a fusion protein with the maltose binding protein (MBP) of Escherichia coli. This recombinant, DEN-2(B)/MBP, was purified and analyzed for its antigenicity, immunogenicity, and ability to protect mice against lethal challenge. The recombinant antigen reacted with a DEN-2 type-specific neutralizing monoclonal antibody (3H5), DEN-2 hyperimmune mouse ascitic fluid, and DEN-2 immune human sera. When administered to mice, DEN-2(B)/MBP elicited a DEN-2 virus neutralizing antibody response that conferred partial protection against challenge infection with a lethal dose of DEN-2 virus administered by intracranial inoculation. In addition, no replication of DEN-2 virus was detectable in the brains of the immunized mice as compared with control mice that were killed six days after challenge. Sera from immunized mice revealed no cross-neutralizing antibody to any of the other DEN serotypes in the plaque-reduction neutralization test. These findings warrant further studies with the DEN-2(B)/MBP antigen as a potential human vaccine candidate. An effective vaccine could prevent thousands of cases of illness and many deaths each year resulting from DEN virus infections.


Comparison of adherent and non-adherent staphylococci in the induction of polymorphonuclear leukocyte activation in vitro.
The ability to consume complement and activate neutrophils was investigated for staphylococci adherent to silicone surfaces and non-adherent staphylococci. Staphylococcus epidermidis strain ATCC 14990 and Staphylococcus aureus strain E 2371 were used in this study. The bacteria were allowed to adhere to silicone catheter segments for 2 h at 37 degrees C. Complement consumption was measured by reduction in serum haemolytic activity against sheep red blood cells. The induction of chemiluminescence was measured after opsonization of the staphylococci in 20% AB-positive human serum for 60 min at 37 degrees C. The bacteria consumed complement to approximately the same extent when adherent to the catheter segments, but more slowly in comparison with planktonic bacteria. When planktonic bacteria were compared, complement was consumed more quickly by S. epidermidis than by S. aureus. Measuring the induction of chemiluminescence by planktonic bacteria, S. epidermidis induced a lower response than S. aureus, while when adherent to the catheter segments the bacteria induced similar responses. These responses were only 15 to 20% of those induced by planktonic bacteria and only slightly higher than the spontaneous chemiluminescence by the neutrophils. Inter-strain variation was found, but all strains induced about the same low chemiluminescence when adherent to the catheter segments. The reduction in inflammatory response caused by adherence of staphylococci to catheter segments may interfere with phagocytosis and elimination of S. epidermidis during the early establishment of a foreign body infection.


Color perception differentiates Alzheimer's Disease (AD) from Vascular Dementia (VaD) patients.
Alzheimer's Disease (AD) and Vascular Dementia (VaD) are the most common causes of dementia in older people. Both diseases appear to have similar clinical symptoms, such as deficits in attention and executive function, but specific cognitive domains are affected. Current cohort studies have shown a close relationship between αβ deposits and age-related macular degeneration (Johnson et al., 2002; Ratnayaka et al., 2015). Additionally, a close link between the thinning of the retinal nerve fiber (RNFL) and AD patients has been described, while it has been proposed that AD patients suffer from a non-specific type of color blindness (Pache et al., 2003). Our study included 103 individuals divided into three groups: A healthy control group (n = 35), AD (n = 32) according to DSM-IV-TR, NINCDS-ADRDA criteria, and VaD (n = 36) based on ΝΙΝDS-AIREN, as well as Magnetic Resonance Imaging (MRI) results. The severity of patient's cognitive impairment, was measured with the Mini-Mental State Examination (MMSE) and was classified according to the Reisberg global deterioration scale (GDS). Visual perception was examined using the Ishihara plates: "Ishihara Color Vision Test - 38 Plate." The three groups were not statistically different for demographic data (age, gender, and education). The Ishihara color blindness test has a sensitivity of 80.6% and a specificity of 87.5% to discriminate AD and VaD patients when an optimal (32.5) cut-off value of performance is used. Ishihara Color Vision Test - 38 Plate is a promising potential method as an easy and not time-consuming screening test for the differential diagnosis of dementia between AD and VaD.


How patients understand physicians' solicitations of additional concerns: implications for up-front agenda setting in primary care.
In the more than 1 billion primary-care visits each year in the United States, the majority of patients bring more than one distinct concern, yet many leave with "unmet" concerns (i.e., ones not addressed during visits). Unmet concerns have potentially negative consequences for patients' health, and may pose utilization-based financial burdens to health care systems if patients return to deal with such concerns. One solution to the problem of unmet concerns is the communication skill known as up-front agenda setting, where physicians (after soliciting patients' chief concerns) continue to solicit patients' concerns to "exhaustion" with questions such as "Are there some other issues you'd like to address?" Although this skill is trainable and efficacious, it is not yet a panacea. This article uses conversation analysis to demonstrate that patients understand up-front agenda-setting questions in ways that hamper their effectiveness. Specifically, we demonstrate that up-front agenda-setting questions are understood as making relevant "new problems" (i.e., concerns that are either totally new or "new since last visit," and in need of diagnosis), and consequently bias answers away from "non-new problems" (i.e., issues related to previously diagnosed concerns, including much of chronic care). Suggestions are made for why this might be so, and for improving up-front agenda setting. Data are 144 videotapes of community-based, acute, primary-care, outpatient visits collected in the United States between adult patients and 20 family-practice physicians.


Sexual and general offending trajectories of men referred for civil commitment.
Policies aimed at managing high-risk offenders, which include sex offenders, often assume they are a homogeneous population. These policies also tend to assume the pattern of offending is the same for all sex offenders, and is stable. This study challenges these assumptions by examining the life course offending trajectories of 780 convicted adult male sexual offenders. The men were referred to the Massachusetts Treatment Center for civil commitment between 1959 and 1984. The changing number of both sexual and any offenses were examined by age using Group-Based Trajectory Modeling. We identified a four-trajectory model for all offending and a four-trajectory model for sexual offending. The identified groups varied in several offending patterns including criminal onset, length of criminal careers, age of peak offending, and time of entry into the treatment center. Late adult onset of sex offending was found to be associated with child molestation, whereas early-onset trajectories were associated with rape. Implications for future research and policy are discussed.


Neck circumference: a useful screening tool of cardiovascular risk in children.
Early identification of cardiovascular risk factors consists an essential target for public health. The current study aims to examine the association between neck circumference and several cardiovascular risk factors and to compare it with well-established anthropometric indices. Demographic, anthropometric (body weight and height, waist, hip and neck circumference [WC, HC and NC, respectively]), biochemical (total cholesterol, high-density lipoprotein [HDL] cholesterol, low-density lipoprotein [LDL] cholesterol, triglycerides [TG], fasting plasma glucose and serum insulin), clinical (pubertal stage, systolic and diastolic blood pressure [SBP and DBP, respectively]) and lifestyle (dietary intake, physical activity level) data were collected from 324 children (51.5% boys; 48.5% girls) aged 9-13 in Greece. Body mass index z-score (BMI z-score), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), homeostasis model assessment (HOMA-IR), quantitative insulin sensitivity check index (QUICKI) and fasting glucose to insulin ratio (FGIR) were calculated. All indices (BMI z-score, NC, WC, HC, WHR and WHtR) were correlated with SBP, HDL and insulin-related indices (insulin, HOMA-IR, QUICKI and FGIR) and all indices except WHR with TG. LDL was correlated with BMI z-score, WC, WHR and WHtR, whereas DBP was correlated with BMI z-score, WC, HC and WHtR. In multivariate analysis, HDL, TG, SBP, insulin, HOMA-IR, QUICKI and FGIR were associated with all anthropometric indices; DBP with WC, HC, NC and WHtR; LDL with BMI z-score, WC, HC and WHtR. NC is associated with most cardiovascular disease risk factors. These associations are comparable with those observed for BMI z-score, WC, HC, WHR and WHtR. NC could be a simple, alternative screening tool of cardiovascular risk in children.


Charybdotoxin and iberiotoxin but not apamin abolish the slow after-hyperpolarization in myenteric plexus neurons.
Myenteric neurons of guinea-pig ileum were studied with intracellular microelectrodes. The specific toxins charybdotoxin, iberiotoxin and apamin were used to characterize the prolonged after-hyperpolarizations of AH neurons in this preparation. Charybdotoxin and iberiotoxin blocked prolonged after-hyperpolarizations in 23 of 24 AH neurons, but apamin had no effect on 5 of 5 AH neurons. Abolition of the after-hyperpolarizations was accompanied by depolarization and increases in input resistances of those AH neurons affected, but the shapes of action potentials were unchanged. The excitability of the AH neurons was enhanced as shown by an increase in the number of action potentials evoked by a 500-ms depolarizing current pulse or by a train of 15-ms depolarizing current pulses (10Hz). The other class of myenteric neurons, S neurons, was also investigated. The 19 S neurons studied fired action potentials only at the start of a 500 ms depolarization, but the toxins had no effect on this behaviour or on their other properties. Intracellular injection of Neurobiotin into the neurons studied and subsequent immunohistochemical staining to localise the calcium-binding protein, calretinin, indicated that all major classes of S neurons were included in the sample. Thus, the prolonged after-hyperpolarizations in AH neurons may be due to opening of a large-conductance (BK) calcium-dependent potassium channel, but similar channels play little or no role in regulation of the excitability of S neurons.


Identification of novel proteins involved in plant cell-wall synthesis based on protein-protein interaction data.
The plant cell wall is mainly composed of polysaccharides, representing the richest source of biomass for future biofuel production. Currently, the majority of the cell-wall synthesis-related (CWSR) proteins are unknown even for model plant Arabidopsis thaliana. We report a computational framework for predicting CWSR proteins based on protein-protein interaction (PPI) data and known CWSR proteins. We predict a protein to be a CWSR protein if it interacts with known CWSR proteins (seeds) with high statistical significance. Using this technique, we predicted 100 candidate CWSR proteins in Arabidopsis thaliana, 8 of which were experimentally confirmed by previous reports. Forty-two candidates have either independent supporting evidence or strong functional relevance to cell-wall synthesis and, hence, are considered as the most reliable predictions. For 33 of the predicted CWSR proteins, we have predicted their detailed functional roles in CWS, based on analyses of their domain architectures, phylogeny, and current functional annotation in conjunction with a literature search. We present the constructed PPIs covering all the known and predicted CWSR proteins at http://csbl.bmb.uga.edu/∼zhouchan/CellWallProtein/. The 42 most reliable candidates provide useful targets to experimentalists for further investigation, and the PPI data constructed in this work provides new information for cell-wall research.


Process for development of multicenter urodynamic studies.
To describe our experiences with a continuous quality improvement process for the standardization of multicenter urodynamic studies (UDSs) in a multi-institutional network. Multicenter UDSs can have considerable variations in testing procedures, training, equipment, and reviewer biases. A quality control process was developed that included protocol development, certification of urodynamic testers, central review to assess compliance with protocol and quality, protocol modifications, standardization of equipment and signal configuration, development of an electronic signal repository, and the development of UDS Interpretation Guidelines. We describe our experience and process in the development and implementation of a standardized UDS protocol in a multicenter surgical trial for stress urinary incontinence. The process included our protocol development, quality control measures, standardization processes, electronic signal repository, and the need for UDS Interpretation Guidelines. A urodynamic testing procedures protocol was implemented successfully by 20 urodynamic testers at nine continence treatment centers. The protocol provides explicit and detailed guidelines for equipment, calibration, patient position, specific annotations, lay language bladder sensation parameters, visual leak point pressure techniques, modifications for prolapse, and data recording. A UDS Interpretation Guidelines document provides specific suggestions for validity and plausibility determination, expected ranges of urodynamic variables, and reasonable agreement of measuring systems. Both documents are available to urodynamic investigators on the Urinary Incontinence Treatment Network website (http://www.uitn.net/resourcesforphysicians.htm). Multicenter UDSs require a continuous quality improvement process and the development of UDS testing procedures and interpretation guidelines.


Memory dysfunction in school-aged children exposed prenatally to antiepileptic drugs.
Prenatal exposure to antiepileptic drugs (AEDs) and in particular valproate (VPA) has been shown to impair intellectual and language development in children, but the impact on memory functioning has not been thoroughly investigated. This study aimed to evaluate memory skills in school-age children who were exposed to AEDs prenatally. The sample comprised of 105 children aged 6 to 8 years. Information on AED exposure, maternal epilepsy, pregnancy, and medical history was prospectively obtained. Children completed a neuropsychological assessment including measures of verbal and nonverbal memory. Children exposed to VPA performed lower than expected on list learning, story recall, and figure recall tasks. Those exposed to VPA in a polytherapy regime achieved poorer verbal memory scores compared with other drug exposure groups. VPA dose was negatively correlated with both verbal and nonverbal memory measures. Language ability predicted performance on all verbal memory measures and VPA dose was an additional predictor of retroactive interference on the list learning task. Performance on figure recall was predicted by exposure to VPA in polytherapy. Children exposed to carbamazepine (CBZ) also showed a higher rate of impairment on nonverbal memory measures. Both verbal and nonverbal memory skills are at risk in children exposed prenatally to VPA, particularly in those exposed to higher VPA doses. There may also be a selective vulnerability of the medial temporal lobe to VPA exposure. Our data highlight the possibility that nonverbal memory may also be affected in children exposed to CBZ. These findings have significant implications for the provision of cognitive and educational strategies to children exposed to AEDs in utero. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Learning Enriched Features for Fast Image Restoration and Enhancement.
Given a degraded input image, image restoration aims to recover the missing high-quality image content. Numerous applications demand effective image restoration, e.g., computational photography, surveillance, autonomous vehicles, and remote sensing. Significant advances in image restoration have been made in recent years, dominated by convolutional neural networks (CNNs). The widely-used CNN-based methods typically operate either on full-resolution or on progressively low-resolution representations. In the former case, spatial details are preserved but the contextual information cannot be precisely encoded. In the latter case, generated outputs are semantically reliable but spatially less accurate. This paper presents a new architecture with a holistic goal of maintaining spatially-precise high-resolution representations through the entire network, and receiving complementary contextual information from the low-resolution representations. The core of our approach is a multi-scale residual block containing the following key elements: (a) parallel multi-resolution convolution streams for extracting multi-scale features, (b) information exchange across the multi-resolution streams, (c) non-local attention mechanism for capturing contextual information, and (d) attention based multi-scale feature aggregation. Our approach learns an enriched set of features that combines contextual information from multiple scales, while simultaneously preserving the high-resolution spatial details. Extensive experiments on six real image benchmark datasets demonstrate that our method, named as MIRNet-v2, achieves state-of-the-art results for a variety of image processing tasks, including defocus deblurring, image denoising, super-resolution, and image enhancement. The source code and pre-trained models are available at https://github.com/swz30/MIRNetv2.


Elemental diet is an effective treatment for eosinophilic esophagitis in children and adolescents.
Eosinophilic esophagitis (EoE), a disorder characterized by eosinophilic infiltration of the esophageal mucosa, has been defined in large part through published case reports and series leading to ambiguity in both diagnostic and treatment options. Corticosteroids, cromolyn, and elemental diet have all been reported as successful treatments for EoE. In this study, we sought to accurately define a population of patients with EoE and then assess their response to elemental diet. A series of patients with chronic symptoms of gastroesophageal reflux disease and an isolated esophageal eosinophilia on esophagogastroduodenoscopy (EGD) were identified. Therapy with a proton pump inhibitor was instituted for 3 months, followed by repeat EGD when symptoms persisted. A 24-h pH probe study was performed, and those with significantly abnormal studies were excluded. The remaining patients were diagnosed with EoE and placed on an elemental diet for 1 month, followed by a repeat EGD. Of 346 patients with chronic gastroesophageal reflux disease symptoms and eosinophils on esophageal biopsy, 51 (14.7%) were ultimately diagnosed with EoE. There was significant improvement in vomiting, abdominal pain, and dysphagia after the elemental diet. The median number of esophageal eosinophils per high-powered field (HPF) decreased from 33.7 before the diet to 1.0 after the diet (p <0.01). The average time to clinical improvement was 8.5 days. Elemental diet resulted in striking improvement in both symptoms and histologic evidence of disease in children and adolescents with EoE, as identified by strict diagnostic criteria.


Continuous rhamnolipid production using denitrifying Pseudomonas aeruginosa cells in hollow-fiber bioreactor.
Rhamnolipids are high-value effective biosurfactants produced by Pseudomonas aeruginosa. Large-scale production of rhamnolipids is still challenging especially under free-cell aerobic conditions in which the highly foaming nature of the culture broth reduces the productivity of the process. Immobilized systems relying on oxygen as electron acceptor have been previously investigated but oxygen transfer limitation presents difficulties for continuous rhamnolipid production. A coupled system using immobilized cells and nitrate instead of oxygen as electron acceptor taking advantage of the ability of P. aeruginosa to perform nitrate respiration was evaluated. This denitrification-based immobilized approach based on a hollow-fiber setup eliminated the transfer limitation problems and was found suitable for continuous rhamnolipid production in a period longer than 1,500 h. It completely eliminated the foaming difficulties related to aerobic systems with a comparable specific productivity of 0.017 g/(g dry cells)-h and allowed easy recovery of rhamnolipids from the cell-free medium.


Membrane potential correlates of sensory perception in mouse barrel cortex.
Neocortical activity can evoke sensory percepts, but the cellular mechanisms remain poorly understood. We trained mice to detect single brief whisker stimuli and report perceived stimuli by licking to obtain a reward. Pharmacological inactivation and optogenetic stimulation demonstrated a causal role for the primary somatosensory barrel cortex. Whole-cell recordings from barrel cortex neurons revealed membrane potential correlates of sensory perception. Sensory responses depended strongly on prestimulus cortical state, but both slow-wave and desynchronized cortical states were compatible with task performance. Whisker deflection evoked an early (<50 ms) reliable sensory response that was encoded through cell-specific reversal potentials. A secondary late (50-400 ms) depolarization was enhanced on hit trials compared to misses. Optogenetic inactivation revealed a causal role for late excitation. Our data reveal dynamic processing in the sensory cortex during task performance, with an early sensory response reliably encoding the stimulus and later secondary activity contributing to driving the subjective percept.


Polarimetry of Pinctada fucata nacre indicates myostracal layer interrupts nacre structure.
The inner layer of many bivalve and gastropod molluscs consists of iridescent nacre, a material that is structured like a brick wall with bricks consisting of crystalline aragonite and mortar of organic molecules. Myostracal layers formed during shell growth at the point of muscle attachment to the shell can be found interspersed within the nacre structure. Little has been done to examine the effect the myostracal layer has on subsequent nacre structure. Here we present data on the structure of the myostracal and nacre layers from a bivalve mollusc, Pinctada fucata. Scanning electron microscope imaging shows the myostracal layer consists of regular crystalline blocks. The nacre before the layer consists of tablets approximately 400 nm thick, while after the myostracal layer the tablets are approximately 500 nm thick. A new technique, imaging polarimetry, indicates that the aragonite crystals within the nacre following the myostracal layer have greater orientation uniformity than before the myostracal layer. The results presented here suggest a possible interaction between the myostracal layer and subsequent shell growth.


Forensic significance of the limbic psychotic trigger reaction.
During the "decade of the brain," competent expert testimony should encompass widely neglected, even novel, neurophysiologically plausible explanations for otherwise unexplainable acts. In the case presented here, a sudden, out-of-character, motiveless, unplanned homicidal attack was committed by a patient who demonstrated flat affect, preserved consciousness, and memory of the episode. Transient autonomic hyperactivation and psychosis were suddenly experienced when the victim happened to move his mouth while eating. Following a sudden memory revival of repetitive but moderate bodily stresses, the patient suffered visceral hallucinations of his entire body being cut into pieces with the delusional belief that he was about to be "cannibalized." The patient's sudden and very transient symptomatology is characteristic of 13 interrelated symptoms and signs (including autonomic, e.g., visceral, hyperactivation and psychosis) proposed as a new subtype of a partial seizure, called "limbic psychotic trigger reaction," which has been consistently delineated thus far in 18 white social loners (14 homicidal men, 3 fire setters, and 1 bank robber), who ruminated about past, moderately painful, but repeated events. This rendered them liable to seizure kindling, particularly of the limbic system. Apparently a post-ictal transient frontal lobe deficiency is secondary to the limbic storm. The forensic impact of seizures on cognition (appreciation of the quality of the act) and on volition is discussed.


S100A13 mediates the copper-dependent stress-induced release of IL-1alpha from both human U937 and murine NIH 3T3 cells.
Copper is involved in the promotion of angiogenic and inflammatory events in vivo and, although recent clinical data has demonstrated the potential of Cu2+ chelators for the treatment of cancer in man, the mechanism for this activity remains unknown. We have previously demonstrated that the signal peptide-less angiogenic polypeptide, FGF1, uses intracellular Cu2+ to facilitate the formation of a multiprotein aggregate that enables the release of FGF1 in response to stress and that the expression of the precursor form but not the mature form of IL-1alpha represses the stress-induced export of FGF1 from NIH 3T3 cells. We report here that IL-1alpha is a Cu2+-binding protein and human U937 cells, like NIH 3T3 cells, release IL-1alpha in response to temperature stress in a Cu2+-dependent manner. We also report that the stress-induced export of IL-1alpha involves the intracellular association with the Cu2+-binding protein, S100A13. In addition, the expression of a S100A13 mutant lacking a sequence novel to this gene product functions as a dominant-negative repressor of IL-1alpha release, whereas the expression of wild-type S100A13 functions to eliminate the requirement for stress-induced transcription. Lastly, we present biophysical evidence that IL-1alpha may be endowed with molten globule character, which may facilitate its release through the plasma membrane. Because Cu2+ chelation also represses the release of FGF1, the ability of Cu2+ chelators to potentially serve as effective clinical anti-cancer agents may be related to their ability to limit the export of these proinflammatory and angiogenic signal peptide-less polypeptides into the extracellular compartment.


A mechanochemical model of striae distensae.
Striae distensae, otherwise known as stretch marks, are common skin lesions found in a variety of clinical settings. They occur frequently during adolescence or pregnancy where there is rapid tissue expansion and in clinical situations associated with corticosteroid excess. Heralding their onset is the appearance of parallel inflammatory streaks aligned perpendicular to the direction of skin tension. Despite a considerable amount of investigative research, the pathogenesis of striae remains obscure. The interpretation of histologic samples - the major investigative tool - demonstrates an association between dermal lymphocytic inflammation, elastolysis, and a scarring response. Yet the primary causal factor in their aetiology is mechanical; either skin stretching due to underlying tissue expansion or, less frequently, a compromised dermis affected by normal loads. In this paper, we investigate the pathogenesis of striae by addressing the coupling between mechanical forces and dermal pathology. We develop a mathematical model that incorporates the mechanical properties of cutaneous fibroblasts and dermal extracellular matrix. By using linear stability analysis and numerical simulations of our governing nonlinear equations, we show that this quantitative approach may provide a realistic framework that may account for the initiating events.


Fitness costs limit the development of resistance to indoxacarb and deltamethrin in Heliothis virescens (Lepidoptera: Noctuidae).
Insecticide resistance in Heliothis virescens (F.) (Lepidoptera: Noctuidae) has been documented from all over the world and is often associated with reduced fitness. Fitness costs could delay the development of resistance depending upon the prevailing conditions. We were interested in establishing whether a field-collected population from Washington County, MS, was resistant to spinosad, indoxacarb, and deltamethrin and whether any such resistance was associated with fitness costs. Bioassays results showed that the insecticides were equally toxic to the field population. Upon laboratory selection (generations [G]3 to G8), the resistance ratio increased only 2-, 3-, and 1-fold for spinosad, deltamethrin, and indoxacarb, respectively, compared with the field population. In contrast, the resistance ratios increased 213-, 65-, and 55-fold compared with an unselected population at G9. The estimated realized heritability (h2) after six generations of selection was 0.17, 0.03, and 0.12, respectively, and the number of generations required for 10-fold increase in LC50 of Spino-SEL, Indoxa-SEL, and Delta-SEL was estimated to be 14.3, 50, and 14.3. Comparison of life traits between the selected and unselected populations revealed that the selected populations laid a significantly lower number of eggs and that a lower percentage of eggs hatched. This also was reflected in both the net replacement rate and the intrinsic rate of population increase, which were both lower for the selected populations. It also was observed that the mean relative growth rate of the larvae was lower for the selected populations; not only did the larvae take longer to pupate but the mean weight of the prepupae from the selected populations was lower. Our data suggest that due to fitness costs the development of resistance to the insecticides was limited such that after six generations of selection the larvae were no less susceptible to the insecticides than the field population although were considerable more resistant than the unselected population.


No evidence for an S cone contribution to acute neuroendocrine and alerting responses to light.
Exposure to even moderately bright short-wavelength light in the evening can strongly suppress the production of melatonin and delay our circadian rhythm. These effects are mediated by the retinohypothalamic pathway, connecting a subset of retinal ganglion cells to the circadian pacemaker in the suprachiasmatic nucleus (SCN) in the brain. These retinal ganglion cells express the photosensitive protein melanopsin, rendering them intrinsically photosensitive (ipRGCs). But ipRGCs also receive input from the classical photoreceptors - the cones and rods. Here, in human participants, we examined whether the short-wavelength-sensitive (S) cones contribute to the neuroendocrine response to light by using stimuli which differed exclusively in the amount of S cone excitation by almost two orders of magnitude (ratio 1:83), but not in the excitation of long-wavelength-sensitive (L) and medium-wavelength-sensitive (M) cones, rods, and melanopsin. We specifically examined the S cones since the previously published action spectra for melatonin suppression [1,2] pointed to a possible role of S cones in addition to melanopsin. We find no evidence for a role of S cones in the acute alerting and melatonin-supressing response to evening light exposure.


An Outbreak of Leaf Spot Caused by Stemphylium solani on Eggplant in Malaysia.
In 2011, a severe gray leaf spot was observed on eggplant (Solanum melongena) in major eggplant growing areas in Malaysia, including the Pahang, Johor, and Selangor states. Disease incidence was >70% in severely infected areas of about 150 ha of eggplant greenhouses and fields examined. Symptoms initially appeared as small (1 to 5 mm diameter), brownish-black specks with concentric circles on the lower leaves. The specks then coalesced and developed into greyish-brown, necrotic lesions, which also appeared on the upper leaves. Eventually, the leaves senesced and were shed. Tissue cut from the edges of leaf spots were surface-sterilized in 1% NaOCl for 2 min, rinsed in sterilized water, dried, and incubated on potato dextrose agar (PDA). Fungal colonies were greyish green to light brown, and produced a yellow pigment. Single, muriform, brown, oblong conidia formed at the terminal end of each conidiophore, were each 21.6 to 45.6 μm long and 11.5 to 21.6 μm wide, and contained 2 to 7 transverse and 1 to 4 longitudinal septa. The conidiophores were tan to light brown and ≤220 μm long. Based on these morphological criteria, 25 isolates of the fungus were identified as Stemphylium solani (1). To produce conidia in culture, 7-day-old single-conidial cultures were established on potato carrot agar (PCA) and V8 juice agar media under an 8-h/16-h light/dark photoperiod at 25°C (4). Further confirmation of the identification was obtained by molecular characterization in which fungal DNA was extracted and the internal transcribed spacer (ITS) region of ribosomal DNA amplified using primers ITS5 and ITS4 (2), followed by direct sequencing. A BLAST search in the NCBI database revealed that the sequence was 99% identical with published ITS sequences for two isolates of S. solani (Accession Nos. AF203451 and HQ840713). The amplified ITS region was deposited in GenBank (JQ736023). Pathogenicity testing of a representative isolate was performed on detached, 45-day-old eggplant leaves of the cv. 125066-X under laboratory conditions. Four fully expanded leaves (one wounded and two non-wounded leaflets/leaf) were placed on moist filter paper in petri dishes, and each leaflet inoculated with a 20-μl drop of a conidial suspension containing 1 × 105 conidia/ml in sterilized, distilled water (3). The leaves were wounded by applying pressure to leaf blades with the serrated edge of forceps. Four control leaves were inoculated similarly with sterilized, distilled water. Inoculated leaves were incubated in humid chambers at 25°C with 95% RH and a 12-h photoperiod. After 7 days, symptoms similar to those observed in the original fields developed on both wounded and non-wounded inoculated leaves, but not on control leaves, and S. solani was reisolated consistently from the symptoms using the same method as the original isolations. Control leaves remained asymptomatic and the fungus was not isolated from these leaves. The pathogenicity testing was repeated with similar results. To our knowledge, this is the first report of S. solani on eggplant in Malaysia. References: (1) B. S. Kim et al. Plant Pathol. J. 20:85, 2004. (2) Y. R. Mehta et al. Curr. Microbiol. 44:323, 2002. (3) B. M. Pryor and T. J. Michailides. Phytopathology 92:406, 2002. (4) E. G. Simmons. CBS Biodiv. Series 6:775, 2007.


The Prevalence of COPD in Individuals with Acute Coronary Syndrome: A Spirometry-Based Screening Study.
The prevalence of COPD among individuals with acute coronary syndrome (ACS) is estimated at 5% to 18%, and COPD appears to be a predictor of poor outcome. Diagnosis of COPD has mostly been based on medical records without spirometry. As COPD is largely undiagnosed and misdiagnosed, the prevalence and clinical significance of COPD in the ACS population has not been reliably assessed. The present study aimed to estimate the prevalence of COPD in patients with ACS and evaluate the accuracy of medical record-based COPD diagnoses. This was a single-centre spirometry screening study for COPD in patients admitted for ACS in the county of Jämtland, Sweden. Patient medical records were reviewed to register previous medical history. Spirometry was performed prior to discharge or at the first follow-up outpatient visit after discharge. COPD was defined as a post-bronchodilator FEV1/FVC of <0.7 or below lower limit of normal. Of 743 eligible patients, 407 performed spirometry. Five percent had COPD according to medical records; 11% and 5% fulfilled spirometric criteria of COPD according to FEV1/FVC of < 0.7 (p = 0.002) and below lower limit of normal definitions, respectively. "COPD according to medical history" had a sensitivity of 23%, specificity of 98%, positive predictive value of 53%, and negative predictive value of 91% compared with spirometric COPD FEV1/FVC of < 0.7 CONCLUSIONS: In patients with ACS, COPD is underdiagnosed and misdiagnosed. We raise concerns regarding the validity of medical record-based COPD in evaluating the biological and clinical association between COPD and coronary disease. ISRCTN number 05697808 (www. controlled-trials.com).


Biomarkers of vitamin B-12 status in NHANES: a roundtable summary.
A roundtable to discuss the measurement of vitamin B-12 (cobalamin) status biomarkers in NHANES took place in July 2010. NHANES stopped measuring vitamin B-12-related biomarkers after 2006. The roundtable reviewed 3 biomarkers of vitamin B-12 status used in past NHANES--serum vitamin B-12, methylmalonic acid (MMA), and total homocysteine (tHcy)--and discussed the potential utility of measuring holotranscobalamin (holoTC) for future NHANES. The roundtable focused on public health considerations and the quality of the measurement procedures and reference methods and materials that past NHANES used or that are available for future NHANES. Roundtable members supported reinstating vitamin B-12 status measures in NHANES. They noted evolving concerns and uncertainties regarding whether subclinical (mild, asymptomatic) vitamin B-12 deficiency is a public health concern. They identified the need for evidence from clinical trials to address causal relations between subclinical vitamin B-12 deficiency and adverse health outcomes as well as appropriate cutoffs for interpreting vitamin B-12-related biomarkers. They agreed that problems with sensitivity and specificity of individual biomarkers underscore the need for including at least one biomarker of circulating vitamin B-12 (serum vitamin B-12 or holoTC) and one functional biomarker (MMA or tHcy) in NHANES. The inclusion of both serum vitamin B-12 and plasma MMA, which have been associated with cognitive dysfunction and anemia in NHANES and in other population-based studies, was preferable to provide continuity with past NHANES. Reliable measurement procedures are available, and National Institute of Standards and Technology reference materials are available or in development for serum vitamin B-12 and MMA.


Magnetism of Ho and Er atoms on close-packed metal surfaces.
We investigated the magnetic properties of individual Ho atoms adsorbed on the (111) surface of Pt, which have been recently claimed to display single ion magnetic behavior. By combining x-ray absorption spectroscopy and magnetic dichroism measurements with ligand field multiplet calculations, we reveal a ground state which is incompatible with long spin relaxation times, in disagreement with former findings. A comparative study of the ground state and magnetic anisotropy of Ho and Er on Pt(111) and Cu(111) emphasizes the different interaction of the 4f orbitals with localized and delocalized substrate states. In particular, we find a striking rotation of the magnetization easy axis for Er, which changes from out of plane on Pt(111) to in plane on Cu(111).


Liquid based material from fine needle aspirates from breast carcinomas offers the possibility of long-time storage without significant loss of immunoreactivity of estrogen and progesterone receptors.
Estrogen receptor (ER) status and progesterone receptor (PgR) status are strong prognostic and predictive markers in breast carcinomas. Steroid receptors are fragile and optimal handling of both cytological and histological material, including fixation, is crucial. Liquid based material offers the possibility to prepare a number of slides from one lesion and is increasingly being used for immunocytochemistry. It also offers the possibility to prepare several smears and to store these at different temperatures as well as storing residual material in the liquid. The samples consisted of fine needle aspirate material from 53 breast carcinomas. Direct smears and liquid based preparations were used in parallel for immunocytochemical detection of ER and PgR receptor status. Slides from liquid suspensions were stored at -20°C and -74°C for 3 and 6 months, respectively. Direct smears were fixed primarily in 4% formalin. Liquid based specimens were post-fixed in 4% formalin. All specimens were subjected to microwave-stimulated epitope retrieval. Antibody concentrations were ER 1:150 and PgR 1:200 for both preparation methods. The immunostaining program was identical for both the methods. Liquid based specimens had a statistically non-significant higher percentage of positive cases compared to direct smears. Specimens prepared from liquid suspensions and stored at -20°C and -74°C for 3 and 6 months, respectively, showed a virtually unchanged ER and PgR reactivity (P = 0.002). Liquid suspensions and liquid based slide preparations seem to offer an optimal pre-fixation and preservation of ER/PgR in breast carcinoma cells. Post-fixation with 4% formalin followed by microwave-stimulated epitope retrieval before immunostaining is recommended. Long-time storage of liquid based specimens at -20°C or -74°C for at least 6 months without significant loss of immunoreactivity is feasible. They may be used as internal positive and negative controls.


miRNA Expression Analyses in Prostate Cancer Clinical Tissues.
A critical challenge in prostate cancer (PCa) clinical management is posed by the inadequacy of currently used biomarkers for disease screening, diagnosis, prognosis and treatment. In recent years, microRNAs (miRNAs) have emerged as promising alternate biomarkers for prostate cancer diagnosis and prognosis. However, the development of miRNAs as effective biomarkers for prostate cancer heavily relies on their accurate detection in clinical tissues. miRNA analyses in prostate cancer clinical specimens is often challenging owing to tumor heterogeneity, sampling errors, stromal contamination etc. The goal of this article is to describe a simplified workflow for miRNA analyses in archived FFPE or fresh frozen prostate cancer clinical specimens using a combination of quantitative real-time PCR (RT-PCR) and in situ hybridization (ISH). Within this workflow, we optimize the existing methodologies for miRNA extraction from FFPE and frozen prostate tissues and expression analyses by Taqman-probe based miRNA RT-PCR. In addition, we describe an optimized method for ISH analyses formiRNA detection in prostate tissues using locked nucleic acid (LNA)- based probes. Our optimized miRNA ISH protocol can be applied to prostate cancer tissue slides or prostate cancer tissue microarrays (TMA).


A Bak-dependent mitochondrial amplification step contributes to Smac mimetic/glucocorticoid-induced necroptosis.
Necroptosis is a form of programmed cell death that critically depends on RIP3 and MLKL. However, the contribution of mitochondria to necroptosis is still poorly understood. In the present study, we discovered that mitochondrial perturbations play a critical role in Smac mimetic/Dexamethasone (Dexa)-induced necroptosis independently of death receptor ligands. We demonstrate that the Smac mimetic BV6 and Dexa cooperate to trigger necroptotic cell death in acute lymphoblastic leukemia (ALL) cells that are deficient in caspase activation due to absent caspase-8 expression or pharmacological inhibition by the caspase inhibitor zVAD.fmk, since genetic silencing or pharmacological inhibition of RIP3 or MLKL significantly rescue BV6/Dexa-induced necroptosis. In addition, RIP3 or MLKL knockout mouse embryonic fibroblasts (MEFs) are protected from BV6/Dexa/zVAD.fmk-induced cell death. In contrast, antagonistic antibodies against the death receptor ligands TNFα, TRAIL or CD95 ligand fail to rescue BV6/Dexa-triggered cell death. Kinetic studies revealed that prior to cell death BV6/Dexa treatment causes hyperpolarization of the mitochondrial membrane potential (MMP) followed by loss of MMP, reactive oxygen species (ROS) production, Bak activation and disruption of mitochondrial respiration. Importantly, knockdown of Bak significantly reduces BV6/Dexa-induced loss of MMP and delays cell death, but not ROS production, whereas ROS scavengers attenuate Bak activation, indicating that ROS production occurs upstream of BV6/Dexa-mediated Bak activation. Consistently, BV6/Dexa treatment causes oxidative thiol modifications of Bak protein. Intriguingly, knockdown or knockout of RIP3 or MLKL protect ALL cells or MEFs from BV6/Dexa-induced ROS production, Bak activation, drop of MMP and disruption of mitochondrial respiration, demonstrating that these mitochondrial events depend on RIP3 and MLKL. Thus, mitochondria might serve as an amplification step in BV6/Dexa-induced necroptosis. These findings provide new insights into the role of mitochondrial dysfunctions during necroptosis and have important implications for the development of novel treatment approaches to overcome apoptosis resistance in ALL.


Speech production in 3-year-old internationally adopted children with unilateral cleft lip and palate.
In the last decade, a large number of children with cleft lip and palate have been adopted to Sweden. A majority of the children were born in China and they usually arrive in Sweden with an unoperated palate. There is currently a lack of knowledge regarding speech and articulation development in this group of children, who also have to deal with a late first language switch. To study consonant proficiency in 3-year-old internationally adopted children with unilateral cleft lip and palate (UCLP) compared with peers with UCLP born in Sweden. Also to study the type and frequency of consonant errors and to perceptually compare velopharyngeal competence between the groups. Thirty-two children born between 2006 and 2010 with UCLP participated in the study-14 adopted from China and 18 children born in Sweden. Both groups were treated by the same cleft palate team. Audio recordings at 3 years of age were perceptually analysed by blinded listeners. Consonant proficiency was measured via per cent consonants correct adjusted for age (PCC-A), per cent correct manners (PCM) and per cent correct places (PCP). The prevalence of audible nasal air leakage and velopharyngeal competence were judged and compared between groups. The type and frequencies of consonant errors related to place and manner of articulation were also analysed. The internationally adopted children had significantly fewer correct consonants compared with the Swedish-born children. This was true for PCC-A, PCP and PCM. This group also had significantly higher prevalence of glottal stops/fricatives and deleted target consonants more often. Also the internationally adopted children had a higher prevalence of incompetent velopharyngeal function. The only outcome variable with similar results in the groups was audible nasal air leakage. The present study indicated that there were significant differences regarding consonant proficiency and velopharyngeal competence between internationally adopted children with a UCLP and their Swedish-born peers with UCLP at the age of 3 years. Internationally adopted children with UCLP should be considered an at risk group for a higher prevalence of speech difficulties than non-adoptees. Thus, it is particularly important to follow this group of children over time. Longitudinal studies of speech and language development in internationally adopted children with UCLP are needed.


Incomplete quality of life data in randomized trials: missing forms.
Analysing quality of life (QOL) data may be complicated for several reasons, such as: repeated measures are obtained; data may be collected on ordered categorical responses; the instrument may have multidimensional scales, and complete data may not be available for all patients. In addition, it may be necessary to integrate QOL with length of life. The major undesirable effects of missing data, in QOL research, are the introduction of biases due to inadequate modes of analysis and the loss of efficiency due to reduced sample sizes. Currently, there is no standard method for handling missing data in QOL studies. In fact, there are very few references to methods of handling missing data in this context. The aim of this paper is to provide an overview of methods for analysing incomplete longitudinal QOL data which have either been presented in the QOL literature or in the missing data literature. These methods of analysis include complete case, available case, summary measures, imputation and likelihood-based approaches. We also discuss the issue of bias and the need for sensitivity analyses.


Tuberculous granulomas are hypoxic in guinea pigs, rabbits, and nonhuman primates.
Understanding the physical characteristics of the local microenvironment in which Mycobacterium tuberculosis resides is an important goal that may allow the targeting of metabolic processes to shorten drug regimens. Pimonidazole hydrochloride (Hypoxyprobe) is an imaging agent that is bioreductively activated only under hypoxic conditions in mammalian tissue. We employed this probe to evaluate the oxygen tension in tuberculous granulomas in four animal models of disease: mouse, guinea pig, rabbit, and nonhuman primate. Following infusion of pimonidazole into animals with established infections, lung tissues from the guinea pig, rabbit, and nonhuman primate showed discrete areas of pimonidazole adduct formation surrounding necrotic and caseous regions of pulmonary granulomas by immunohistochemical staining. This labeling could be substantially reduced by housing the animal under an atmosphere of 95% O(2). Direct measurement of tissue oxygen partial pressure by surgical insertion of a fiber optic oxygen probe into granulomas in the lungs of living infected rabbits demonstrated that even small (3-mm) pulmonary lesions were severely hypoxic (1.6 +/- 0.7 mm Hg). Finally, metronidazole, which has potent bactericidal activity in vitro only under low-oxygen culture conditions, was highly effective at reducing total-lung bacterial burdens in infected rabbits. Thus, three independent lines of evidence support the hypothesis that hypoxic microenvironments are an important feature of some lesions in these animal models of tuberculosis.


Comparing the Knotless Tension Band and the Traditional Stainless Steel Wire Tension Band Fixation for Medial Malleolus Fractures: A Retrospective Clinical Study.
The traditional stainless steel wire tension band (WTB) has been popularized for small avulsion fractures at the medial malleolus. Despite the tension band principle creating a stable construct, complications continue to arise utilizing the traditional stainless steel WTB with patients experiencing hardware irritation at the tension band site and subsequent hardware removal. Coupled with hardware irritation is fatigue failure with the wire. The goal of this investigation was to retrospectively compare this traditional wire technique to an innovative knotless tension band (KTB) technique in order to decrease costly complications. A total of 107 patients were reviewed with a minimum follow-up of 1 year. Outcome measures include descriptive data, fracture classification, results through economic costs, and fixation results (including hardware status, healing status, pain status, and time to healing). The KTB group had a 13% lower true cost as compared to the WTB group while the fixation results were equivocal for the measured outcomes. Our results demonstrate that the innovative KTB is comparable to the traditional WTB while offering a lower true cost, an irritation free reduction all without the frustration of returning to the operating room for additional hardware removal, which averages approximately to $8,288.


Application of bioreactance for cardiac output assessment during exercise in healthy individuals.
In patients with cardiac failure, bioreactance-based cardiac output (CO) monitoring provides a valid non-invasive method for assessing cardiac performance during exercise. The purpose of this study was to evaluate the efficacy of this technique during strenuous exercise in healthy, trained individuals. Fourteen recreational cyclists, mean (SD) age of 34 (8) years and relative peak oxygen uptake of (VO(2)) 56 (6) ml kg(-1) min(-1), underwent incremental maximal exercise testing, whilst CO was recorded continuously using a novel bioreactance-based device (CO(bio)). The CO(bio) was evaluated against relationship with VO(2), theoretical calculation of arterial-venous oxygen difference (C(a - v) O(2)) and level of agreement with an inert gas rebreathing method (CO(rb)) using a Bland-Altman plot. Bioreactance-based CO measurement was practical and straightforward in application, although there was intermittent loss of electrocardiograph signal at high-intensity exercise. At rest and during exercise, CO(bio) was strongly correlated with VO(2) (r = 0.84; P < 0.001), however, there was evidence of systematic bias with CO(bio) providing lower values than CO(rb); mean bias (limits of agreement) -19% (14.6 to -53%). Likewise, calculated (C(a - v) O(2)) was greater when determined using CO(bio) than CO(rb) (P < 0.001), although both devices provided values in excess of those reported in invasive studies. Bioreactance-based determination of CO provides a pragmatic approach to the continuous assessment of cardiac performance during strenuous exercise in trained individuals. Our findings, however, suggest that further work is needed to refine the key measurement determinants of CO using this device to improve measurement accuracy in this setting.


Bio-inspired CO2 conversion by iron sulfide catalysts under sustainable conditions.
The mineral greigite presents similar surface structures to the active sites found in many modern-day enzymes. We show that particles of greigite can reduce CO2 under ambient conditions into chemicals such as methanol, formic, acetic and pyruvic acid. Our results also lend support to the Origin of Life theory on alkaline hydrothermal vents.


Optimizing PEGylation of TiO2 Nanocrystals through a Combined Experimental and Computational Study.
PEGylation of metal oxide nanoparticles is the common approach to improve their biocompatibility and in vivo circulation time. In this work, we present a combined experimental and theoretical study to determine the operating condition that guarantee very high grafting densities, which are desirable in any biomedical application. Moreover, we present an insightful conformational analysis spanning different coverage regimes and increasing polymer chain lengths. Based on 13C NMR measurements and molecular dynamics simulations, we show that classical and popular models of polymer conformation on surfaces fail in determining the mushroom-to-brush transition point and prove that it actually takes place only at rather high grafting density values.


Pierce's Disease of Grapevines: A Review of Control Strategies and an Outline of an Epidemiological Model.
Xylella fastidiosa is a notorious plant pathogenic bacterium that represents a threat to crops worldwide. Its subspecies, Xylella fastidiosa subsp. fastidiosa is the causal agent of Pierce's disease of grapevines. Pierce's disease has presented a serious challenge for the grapevine industry in the United States and turned into an epidemic in Southern California due to the invasion of the insect vector Homalodisca vitripennis. In an attempt to minimize the effects of Xylella fastidiosa subsp. fastidiosa in vineyards, various studies have been developing and testing strategies to prevent the occurrence of Pierce's disease, i.e., prophylactic strategies. Research has also been undertaken to investigate therapeutic strategies to cure vines infected by Xylella fastidiosa subsp. fastidiosa. This report explicitly reviews all the strategies published to date and specifies their current status. Furthermore, an epidemiological model of Xylella fastidiosa subsp. fastidiosa is proposed and key parameters for the spread of Pierce's disease deciphered in a sensitivity analysis of all model parameters. Based on these results, it is concluded that future studies should prioritize therapeutic strategies, while investments should only be made in prophylactic strategies that have demonstrated promising results in vineyards.


Genetic architecture of HIV-1 genes circulating in north India & their functional implications.
This review presents data on genetic and functional analysis of some of the HIV-1 genes derived from HIV-1 infected individuals from north India (Delhi, Punjab and Chandigarh). We found evidence of novel B/C recombinants in HIV-1 LTR region showing relatedness to China/Myanmar with 3 copies of Nfκb sites; B/C/D mosaic genomes for HIV-1 Vpr and novel B/C Tat. We reported appearance of a complex recombinant form CRF_02AG of HIV-1 envelope sequences which is predominantly found in Central/Western Africa. Also one Indian HIV-1 envelope subtype C sequence suggested exclusive CXCR4 co-receptor usage. This extensive recombination, which is observed in about 10 per cent HIV-1 infected individuals in the Vpr genes, resulted in remarkably altered functions when compared with prototype subtype B Vpr. The Vpu C was found to be more potent in causing apoptosis when compared with Vpu B when analyzed for subG1 DNA content. The functional implications of these changes as well as in other genes of HIV-1 are discussed in detail with possible implications for subtype-specific pathogenesis highlighted.


Stereostructure-activity studies on agonists at the AMPA and kainate subtypes of ionotropic glutamate receptors.
(S)-Glutamic acid (Glu), the major excitatory neurotransmitter in the central nervous system, operates through ionotropic as well as metabotropic receptors and is considered to be involved in certain neurological disorders and degenerative brain diseases that are currently without any satisfactory therapeutic treatment. Until recently, development of selective Glu receptor agonists had mainly been based on lead compounds, which were frequently naturally occurring excitants structurally related to Glu. These Glu receptor agonists generally contain heterocyclic acidic moieties, which has stimulated the use of bioisosteric replacement approaches for the design of subtype-selective agonists. Furthermore, most of these leads are conformationally restricted and stereochemically well-defined Glu analogs. Crystallization of the agonist binding domain of the GluR2 subunit of the (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor subtype of ionotropic Glu receptors in the presence or absence of an agonist has provided important information about ligand-receptor interaction mechanisms. The availability of these binding domain crystal structures has formed the basis for rational design of ligands, especially for the AMPA and kainate subtypes of ionotropic Glu receptors. This mini-review will focus on structure-activity relationships on AMPA and kainate receptor agonists with special emphasis on stereochemical and three-dimensional aspects.


Patient and nurse perceptions of stressors in the intensive care unit.
The objective of the study was to determine the perceptions of a group of patients on intensive care units' (ICUs) stressors and the perceptions of nurses on ICU patients' stressors in Turkey, and compare the differences in patients' and nurses' perception of the stressors in ICUs. In this descriptive study, 155 patients who were admitted to medical or surgical ICUs and 152 nurses who are employed in the same units of two training and research hospitals in Turkey were enrolled in this study. The ICU Environmental Stressor Scale (ICUESS) was used to determine intensive care stressors. According to total ICUESS mean scores, patients (91.41 ± 34.91) perceived significantly less stress than the ICU nurses (133.23 ± 32.20) perceived them to have. Both patients and nurses ranked 'fear of death' as the greatest stressor. Physiological stressors were identified as the most important stressors by both patients and nurses. Patients and nurses in medical ICUs were more affected by stressors than their counterparts in surgical ICUs. Patients with unplanned or emergency admissions perceived higher stress than that of patients with planned admissions. Several factors could help reduce these stressors, such as having familiar arrangements, humane ICU environment, individual patient assessments and appropriate nursing interventions.


Fitting the Fractional Polynomial Model to Non-Gaussian Longitudinal Data.
As in cross sectional studies, longitudinal studies involve non-Gaussian data such as binomial, Poisson, gamma, and inverse-Gaussian distributions, and multivariate exponential families. A number of statistical tools have thus been developed to deal with non-Gaussian longitudinal data, including analytic techniques to estimate parameters in both fixed and random effects models. However, as yet growth modeling with non-Gaussian data is somewhat limited when considering the transformed expectation of the response via a linear predictor as a functional form of explanatory variables. In this study, we introduce a fractional polynomial model (FPM) that can be applied to model non-linear growth with non-Gaussian longitudinal data and demonstrate its use by fitting two empirical binary and count data models. The results clearly show the efficiency and flexibility of the FPM for such applications.


Virotherapy Research in Germany: From Engineering to Translation.
Virotherapy is a unique modality for the treatment of cancer with oncolytic viruses (OVs) that selectively infect and lyse tumor cells, spread within tumors, and activate anti-tumor immunity. Various viruses are being developed as OVs preclinically and clinically, several of them engineered to encode therapeutic proteins for tumor-targeted gene therapy. Scientists and clinicians in German academia have made significant contributions to OV research and development, which are highlighted in this review paper. Innovative strategies for "shielding," entry or postentry targeting, and "arming" of OVs have been established, focusing on adenovirus, measles virus, parvovirus, and vaccinia virus platforms. Thereby, new-generation virotherapeutics have been derived. Moreover, immunotherapeutic properties of OVs and combination therapies with pharmacotherapy, radiotherapy, and especially immunotherapy have been investigated and optimized. German investigators are increasingly assessing their OV innovations in investigator-initiated and sponsored clinical trials. As a prototype, parvovirus has been tested as an OV from preclinical proof-of-concept up to first-in-human clinical studies. The approval of the first OV in the Western world, T-VEC (Imlygic), has further spurred the involvement of investigators in Germany in international multicenter studies. With the encouraging developments in funding, commercialization, and regulatory procedures, more German engineering will be translated into OV clinical trials in the near future.


Disseminated angiolymphoid hyperplasia with eosinophilia: a case report.
A 37-year-old Cantonese man presented with pruritic erythematous papules and nodules on his face, limbs, and trunk that had been present for 10 years and aggravated for 2 years. More nodules were noticed where the skin was scratched and traumatized. The lesions were alleviated temporarily, but they did not subside entirely without therapy. The lesions responded to treatment with intravenous dexamethasone. Histopathology results indicated angiolymphoid hyperplasia with eosinophilia (ALHE), and the patient was diagnosed with disseminated ALHE (DALHE). His lesions ameliorated after treatment with prednisone.


Dating the origin and dispersal of hepatitis B virus infection in humans and primates.
The origin of hepatitis B virus (HBV) infection in humans and other primates remains largely unresolved. Understanding the origin of HBV is crucial because it provides a framework for studying the burden, and subsequently the evolution, of HBV pathogenicity with respect to changes in human population size and life expectancy. To investigate this controversy we examined the relationship between HBV phylogeny and genetic diversity of modern humans, investigated the timescale of global HBV dispersal, and tested the hypothesis of HBV-human co-divergence. We find that the global distribution of HBV genotypes and subgenotypes are consistent with the major prehistoric modern human migrations. We calibrate the HBV molecular clock using the divergence times of different indigenous human populations based on archaeological and genetic evidence and show that HBV jumped into humans around 33,600 years ago; 95% higher posterior density (HPD): 22,000-47,100 years ago (estimated substitution rate: 2.2 × 10(-6) ; 95% HPD: 1.5-3.0 × 10(-6) substitutions/site/year). This coincides with the origin of modern non-African humans. Crucially, the most pronounced increase in the HBV pandemic correlates with the global population increase over the last 5,000 years. We also show that the non-human HBV clades in orangutans and gibbons resulted from cross-species transmission events from humans that occurred no earlier than 6,100 years ago. Our study provides, for the first time, an estimated timescale for the HBV epidemic that closely coincides with dates of human dispersals, supporting the hypothesis that HBV has been co-expanding and co-migrating with human populations for the last 40,000 years. (HEPATOLOGY 2013).


The future of death in America.
Population mortality forecasts are widely used for allocating public health expenditures, setting research priorities, and evaluating the viability of public and private pensions, and health care financing systems. In part because existing methods forecast less accurately when based on more information, most forecasts are still based on simple linear extrapolations that ignore known biological risk factors and other prior information. We adapt a Bayesian hierarchical forecasting model capable of including more known health and demographic information than has previously been possible. This leads to the first age- and sex-specific forecasts of American mortality that simultaneously incorporate, in a formal statistical model, the effects of the recent rapid increase in obesity, the steady decline in tobacco consumption, and the well known patterns of smooth mortality age profiles and time trends. Formally including new information in forecasts can matter a great deal. For example, we estimate an increase in male life expectancy at birth from 76.2 years in 2010 to 79.9 years in 2030, which is 1.8 years greater than the U.S. Social Security Administration projection and 1.5 years more than U.S. Census projection. For females, we estimate more modest gains in life expectancy at birth over the next twenty years from 80.5 years to 81.9 years, which is virtually identical to the Social Security Administration projection and 2.0 years less than U.S. Census projections. We show that these patterns are also likely to greatly affect the aging American population structure. We offer an easy-to-use approach so that researchers can include other sources of information and potentially improve on our forecasts too.


Dissecting the antibacterial activity of oxadiazolone-core derivatives against Mycobacterium abscessus.
Mycobacterium abscessus (M. abscessus), a rapidly growing mycobacterium, is an emergent opportunistic pathogen responsible for chronic bronchopulmonary infections in individuals with respiratory diseases such as cystic fibrosis. Most treatments of M. abscessus pulmonary infections are poorly effective due to the intrinsic resistance of this bacteria against a broad range of antibiotics including anti-tuberculosis agents. Consequently, the number of drugs that are efficient against M. abscessus remains limited. In this context, 19 oxadiazolone (OX) derivatives have been investigated for their antibacterial activity against both the rough (R) and smooth (S) variants of M. abscessus. Several OXs impair extracellular M. abscessus growth with moderated minimal inhibitory concentrations (MIC), or act intracellularly by inhibiting M. abscessus growth inside infected macrophages with MIC values similar to those of imipenem. Such promising results prompted us to identify the potential target enzymes of the sole extra and intracellular inhibitor of M. abscessus growth, i.e., compound iBpPPOX, via activity-based protein profiling combined with mass spectrometry. This approach led to the identification of 21 potential protein candidates being mostly involved in M. abscessus lipid metabolism and/or in cell wall biosynthesis. Among them, the Ag85C protein has been confirmed as a vulnerable target of iBpPPOX. This study clearly emphasizes the potential of the OX derivatives to inhibit the extracellular and/or intracellular growth of M. abscessus by targeting various enzymes potentially involved in many physiological processes of this most drug-resistant mycobacterial species.


Reducing multi-photon rates in pulsed down-conversion by temporal multiplexing.
We present a simple technique to reduce the emission rate of higher-order photon events from pulsed spontaneous parametric down-conversion. The technique uses extra-cavity control over a mode locked ultrafast laser to simultaneously increase repetition rate and reduce the energy of each pulse from the pump beam. We apply our scheme to a photonic quantum gate, showing improvements in the non-classical interference visibility for 2-photon and 4-photon experiments, and in the quantum-gate fidelity and entangled state production in the 2-photon case.


HIV reservoirs and latency models.
The main impediment to a cure for HIV is the existence of long-lasting treatment resistant viral reservoirs. In this review, we discuss what is currently known about reservoirs, including their formation and maintenance, while focusing on latently infected CD4+ T cells. In addition, we compare several different in vivo and in vitro models of latency. We comment on how each model may reflect the properties of reservoirs in vivo, especially with regard to cell phenotype, since recent studies demonstrate that multiple CD4+ T cell subsets contribute to HIV reservoirs and that with HAART and disease progression the relative contribution of different subsets may change. Finally, we focus on the direct infection of resting CD4+ T cells as a source of reservoir formation and as a model of latency, since recent results help explain the misconception that resting CD4+ T cells appeared to be resistant to HIV in vitro.


An atopic dermatitis-like skin disease with hyper-IgE-emia develops in mice carrying a spontaneous recessive point mutation in the Traf3ip2 (Act1/CIKS) gene.
Spontaneous mutant mice that showed high levels of serum IgE and an atopic dermatitis (AD)-like skin disease were found in a colony of the KOR inbred strain that was derived from Japanese wild mice. No segregation was observed between hyper-IgE-emia and dermatitis in (BALB/c x KOR mutant) N(2) mice, suggesting that the mutation can be attributed to a single recessive locus, which we designated adjm (atopic dermatitis from Japanese mice). All four adjm congenic strains in different genetic backgrounds showed both hyper-IgE-emia and dermatitis, although the disease severity varied among strains. Linkage analysis using (BALB/c x KOR-adjm/adjm) N(2) mice restricted the potential adjm locus to the 940 kb between D10Stm216 and D10Stm238 on chromosome 10. Sequence analysis of genes located in this region revealed that the gene AI429613, which encodes the mouse homologue of the human TNFR-associated factor 3-interacting protein 2 (TRAF3IP2) protein (formerly known as NF-kappaB activator 1/connection to IkappaB kinase and stress-activated protein kinase/Jun kinase), carried a single point mutation leading to the substitution of a stop codon for glutamine at amino acid position 214. TRAF3IP2 has been shown to function as an adaptor protein in signaling pathways mediated by the TNFR superfamily members CD40 and B cell-activating factor in epithelial cells and B cells as well as in the IL-17-mediated signaling pathway. Our results suggest that malfunction of the TRAF3IP2 protein causes hyper-IgE-emia through the CD40- and B cell-activating factor-mediated pathway in B cells and causes skin inflammation through the IL-17-mediated pathway. This study demonstrates that the TRAF3IP2 protein plays an important role in AD and suggests the protein as a therapeutic target to treat AD.


Nutraceutical Characterization of Anthocyanin-Rich Fruits Produced by "Sun Black" Tomato Line.
Tomato (Solanum lycopersicum L.) is one of the most cultivated vegetable in the world and it represents a large source of bioactive compounds, including carotenoids and polyphenols (phenolic acids and flavonoids). However, the concentration of flavonoids in tomato is considered sub-optimal, particularly because anthocyanins are not generally present. Therefore, this crop has been the object of an intense metabolic engineering in order to obtain anthocyanin-enriched tomatoes by using either breeding or transgenic strategies. Some wild tomato species, such as S. chilense and S. cheesmaniae, biosynthesize anthocyanins in the fruit sub-epidermal tissue, and some alleles from those genotypes have been introgressed into a new developed purple tomato line, called "Sun Black" (SB). It is a tomato line with a purple skin color, both in green and in red fruit stages, due to the biosynthesis of anthocyanins in the peel, and a normal red color pulp, with a taste just like a traditional tomato. SB is the result of a breeding programme and it is not a genetically modified (GM) product. We report the chemical characterization and structure elucidation of the attractive anthocyanins found in the peel of SB tomato, as well as other bioactive compounds (carotenoids, polyphenols, vitamin C) of the whole fruit. Using one- and two-dimensional NMR experiments, the two main anthocyanins were identified to be petunidin 3-O-[6″-O-(4‴-O-E-p-coumaroyl-α-rhamnopyranosyl) -β-glucopyranoside]-5-O-β-glucopyranoside (petanin) and malvidin 3-O-[6″-O-(4‴-O-E-p-coumaroyl-α-rhamnopyranosyl)-β-glucopyranoside]-5-O-β-glucopyranoside (negretein). The total anthocyanins in the whole ripe fruit was 1.2 mg/g dry weight (DW); 7.1 mg/100 g fresh weight (FW). Chlorogenic acid (the most abundant phenolic acid) was 0.6 mg/g DW; 3.7 mg/100 g FW. The main flavonol, rutin was 0.8 mg/g DW; 5 mg/100 g FW. The total carotenoid content was 211.3 μg/g DW; 1,268 μg/100 g FW. The total phenolic content was 8.6 mg/g DW; 52.2 mg/100 g FW. The vitamin C content was 37.3 mg/100 g FW. The antioxidant activities as measured by the TEAC and ORAC assays were 31.6 and 140.3 μmol TE/g DW, respectively (193 and 855.8 μmol TE/100 g FW, respectively). The results show the unique features of this new tomato genotype with nutraceutical properties.


Microstructure of a poled surface-relief grating and its electro-optic response.
The microstructure of a poled surface-relief grating of an azobenzene side-chain polymer film is investigated. From the in situ monitoring of diffraction efficiency and second-harmonic generation, as well as dynamic-contact electrostatic force microscopy images, the point group symmetry of C2nu is identified. The polarization-dependent electro-optic measurement of the reflected diffraction order further confirms the optically biaxial structure of the poled surface-relief grating.


Analysis of human monoclonal antibodies derived from lymphocytes of patients with cancer.
Human lymphocytes from tumor-bearing patients and normal individuals have been fused with the NS-1 mouse myeloma line or the LICR -LON- HMY2 ( LICR -2) or SK0 -007 human cell lines. For a given number of lymphocytes, fusions with NS-1 produced 8 times more clones than fusions with LICR -2 and greater than 20 times more clones than fusions with SK0 -007. The percentage of clones that secrete human immunoglobulin (Ig) and the range of Ig production were comparable for clones derived from the three myeloma/lymphoblastoid lines. Clones derived from fusions with LICR -2 and SK0 -007 were found to secrete new species of light and heavy Ig chains in addition to those of the myeloma/lymphoblastoid lines, and clones derived from fusions with NS-1 secreted human Ig and contained both mouse and human chromosomes, which indicates that true hybrid cells were derived from fusions with each of the myeloma/lymphoblastoid lines under study. The stability of Ig production was similar for clones derived from fusions with NS-1, LICR -2, or SK0 -007; these results were comparable to those obtained with standard mouse/mouse hybrids. Stable clones producing human monoclonal antibodies that react with cell surface, cytoplasmic, cytoskeletal, nuclear, or nucleolar antigens have been isolated from tumor-bearing patients and normal individuals. A number of human monoclonal antibodies reactive with cytoskeletal antigens appear to be directed against components of the intermediate filament family. Techniques for the production of human monoclonal antibody appear to be sufficiently advanced to initiate a serological dissection of the humoral immune response to cancer.


Management of Advanced Bladder Cancer: An Update.
Bladder cancer is the sixth most common cancer in the United States; therefore, the majority of clinicians working in the oncology setting will care for this patient population. Unfortunately, treatment plans, especially in the advanced setting, lack consistency. This, along with the advanced age and comorbidities of most bladder cancer patients, can provide challenges for clinicians when developing treatment plans. In the past 2 years, new drug approvals, specifically those for immune checkpoint inhibitors, have changed the treatment landscape for bladder cancer for the first time since the 1980s. This review article outlines the current management for muscle-invasive and metastatic bladder cancer, while also highlighting future considerations in this disease space. It is imperative that oncology advanced practice providers are up to date with these new changes and have a sound understanding of treatment principles for patients with advanced bladder cancer in order to deliver the safest and most effective care.


Self-efficacy and consumer satisfaction with housing.
During clinical recovery mental health consumers express increasing interest in assuming control over their community living arrangements. Despite recent policy initiatives toward consumer empowerment in housing services and supports, few studies have explored empowerment issues, such as self-efficacy, in relation to housing satisfaction. This study explored the extent to which specific areas of support and self-efficacy predict consumer satisfaction with housing. This study also explored how different types of housing, and consumer housing preferences, also explain consumer satisfaction with housing. One-hundred twenty-five randomly selected consumers completed structured interviews. As hypothesized, hierarchical multiple predictor regression analyses revealed type of housing and self-efficacy as significant predictor variables. The total regression equation accounted for 67 percent of the explained variance in housing satisfaction. Chi-square analyses across housing groups indicated that consumers prefer less restrictive residential settings. Findings suggest that consumers prefer less restrictive housing, as such relate in part to increasing levels of self-efficacy. Further study is recommended to explore how self-efficacy may best be promoted across different clinical groups and different residential settings.


Overexpression of human arginine decarboxylase rescues human mesenchymal stem cells against H₂O₂ toxicity through cell survival protein activation.
In this study, we explored the potentiality of human arginine decarboxylase (ADC) to enhance the survival of mesenchymal stem cells (MSCs) against unfavorable milieu of host tissues as the low survival of MSCs is the issue in cell transplantation therapy. To address this, human MSCs overexpressing human ADC were treated with H2O2 and the resultant intracellular events were examined. First, we examined whether human ADC is overexpressed in human MSCs. Then, we investigated cell survival or death related events. We found that the overexpression of human ADC increases formazan production and reduces caspase 3 activation and the numbers of FITC, hoechst, or propidium iodide positive cells in human MSCs exposed to H2O2. To elucidate the factors underlying these phenomena, AKT, CREB, and BDNF were examined. We found that the overexpression of human ADC phosphorylates AKT and CREB and increases BDNF level in human MSCs exposed to H2O2. The changes of these proteins are possibly relevant to the elevation of agmatine. Collectively, our data demonstrate that the overexpression of human ADC stimulates pro-survival factors to protect human MSCs against H2O2 toxicity. In conclusion, the present findings support that ADC can enhance the survival of MSCs against hostile environment of host tissues.